Growth factors of the Epidermal Growth Factor family play pivotal roles in development of the nervous system and the cardiovascular system. Interest in the functions of these hormones and receptors in the mammary gland is driven by the importance of the Epidermal Growth Factor Receptor and the related receptor ErbB2 in breast cancer and in other carcinomas. Both receptors are under intensive investigation as therapeutic targets in cancer, and the latter is the validated therapeutic target for the FDA-approved drug Trastuzumab/Herceptin. In contrast to Epidermal Growth Factor Receptor and ErbB2, the related receptor ErbB4 seems to be linked to terminal differentiation of the mammary gland, and may antagonize carcinogenesis. We will determine whether ErbB4 is important as a negative or positive regulator in human breast cancer and in a mouse model for ErbB2-mediated carcinogenesis, and will determine what the normal functions are for ErbB4 in the mammary gland. Aim 1 will determine the associations of ErbB4 expression with clinical outcome in a large panel of human breast carcinoma specimens with long-term followup data. The effect of gene disruption of ErbB4 on the timing of MMTV-Neu induced carcinoma in transgenic mice will be determined. Aim 2 will determine the mammary phenotypes associated with disruption of ErbB4 in mouse. Aim 3 will investigate signal transduction mechanisms linked to processes that are found to be important in Aim 2. The results will indicate whether ErbB4 expression has prognostic significance, and will suggest whether modulation of ErbB4-activated pathways will be beneficial to cancer patients. Since ErbB4 is also important in developing an adult nervous system, neuromuscular junction, and heart, information about the mechanisms of ErbB4 signal transduction may help develop treatments for nerve and muscle damage disorders, and cardiovascular disorders.